This proposal aims to investigate the folding mechanism of the protein interleukin-1beta. Specifically, the roles of topology, solvation, and energetics in forming the free energy landscape will be analyzed. The issue of cooperativity in the folding mechanism and in the stabilization of the intermediate and native state will also be addressed, specifically, that of a hydrogen-bonded network. Molecular dynamics simulations with several protein models designed to capture and isolate the components of topology, solvation, energetics, and cooperativity will be run to determine their relative importance to the folding mechanism and stability of interleukin-1beta. The simulated data will be generated in parallel with NMR and hydrogen exchange studies by Dr. Jennings' lab, providing the applicant a chance to approach the problem with both theory and experiment. This protein is a significant cytokine that functions extracellularly throughout the body. It is involved in growth regulation and inflammation. Studies that characterize its folding mechanism may provide insight to why this protein is prone to aggregation. Understanding how this protein folds will also be of use to understanding the general protein folding problem. [unreadable] [unreadable]